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Most complex diseases involve genetic and environmental risk factors, engage multiple cells and tissues, and follow a polygenic or omnigenic model depicting numerous genes contributing to pathophysiology. These multidimensional complexities pose challenges to traditional approaches that examine individual factors. In turn, multitissue multiomics systems biology has emerged to comprehensively elucidate within- and cross-tissue molecular networks underlying gene-by-environment interactions and contributing to complex diseases. The power of systems biology in retrieving novel insights and formulating new hypotheses has been well documented. However, the field faces various challenges that call for debate and action. In this opinion article, I discuss the concepts, benefits, current state, and challenges of the field and point to the next steps toward network-based systems medicine.